Specific cell killing can be essential for the successful treatment of a variety of diseases in mammalian subjects. Typical examples of this are in the treatment of malignant diseases such as sarcomas and carcinomas. However the selective elimination of certain cell types can also play a key role in the treatment of many other diseases, especially immunological, hyperplastic and/or other neoplastic diseases.
The most common methods of selective treatment are currently surgery, chemotherapy and external beam irradiation. Targeted endo-radionuclide therapy is, however, a promising and developing area with the potential to deliver highly cytotoxic radiation to unwanted cell types. The most common forms of radiopharmaceutical currently authorised for use in humans employ beta-emitting and/or gamma-emitting radionuclides. There has, however, been a recent surge in interest in the use of alpha-emitting radionuclides in therapy because of their potential for more specific cell killing. One alpha-emitting nuclide in particular, radium-223 (223Ra) has proven remarkably effective, particularly for the treatment of diseases associated with the bone and bone-surface.
The radiation range of typical alpha emitters in physiological surroundings is generally less than 100 micrometers, the equivalent of only a few cell diameters. This makes these nuclei well suited for the treatment of tumours, including micrometastases, because little of the radiated energy will pass beyond the target cells and thus damage to surrounding healthy tissue might be minimised (see Feinendegen et al., Radiat Res 148:195-201 (1997)). In contrast, a beta particle has a range of 1 mm or more in water (see Wilbur, Antibody Immunocon Radiopharm 4: 85-96 (1991)).
The energy of alpha-particle radiation is high compared to beta particles, gamma rays and X-rays, typically being 5-8 MeV, or 5 to 10 times that of a beta particle and 20 or more times the energy of a gamma ray. Thus, this deposition of a large amount of energy over a very short distance gives α-radiation an exceptionally high linear energy transfer (LET), high relative biological efficacy (RBE) and low oxygen enhancement ratio (OER) compared to gamma and beta radiation (see Hall, “Radiobiology for the radiologist”, Fifth edition, Lippincott Williams & Wilkins, Philadelphia Pa., USA, 2000). This explains the exceptional cytotoxicity of alpha emitting radionuclides and also imposes stringent demands on the level of purity required where an isotope is to be administered internally. This is especially the case where any contaminants may also be alpha-emitters, and most particularly where long half-life alpha emitters may be present, since these can potentially cause significant damage over an extended period of time.
One radioactive decay chain leading to 223Ra, which has been used as a source for this isotope in small quantities, is indicated below. The table shows the element, molecular weight (Mw), decay mode (mode) and Half-life (in years (y) or days (d)) for 223Ra and its two precursor isotopes. This preparation begins from 227Ac, which is itself found only in traces in uranium ores, being part of the natural decay chain originating at 235U. One ton of uranium ore contains about a tenth of a gram of actinium and thus although 227Ac is found naturally, it is more commonly made by the neutron irradiation of 226Ra in a nuclear reactor.

It can be seen from this illustration that 227Ac, with a half-life of over 20 years, is a very dangerous potential contaminant with regard to preparing 223Ra from the above decay chain for pharmaceutical use. In particular, although 227Ac itself is a beta-emitter, its long half-life means that even very low activities represent a significant lifetime radiation exposure, and furthermore, once it decays, the resulting daughter nuclei generate a further 5 alpha-decays and 2 beta-decays before reaching stable 207Pb. These are illustrated in the table below:
Nuclide227Th223Ra219Rn215Po211Pb211Bi207Tl207Pb½-life18.7 d11.4 d4.0 s1.8 ms36.1 m2.2 m4.8 mstableα-energy/MeV6.155.646.757.396.55β-energy1.371.42(max)/MeVEnergy %17.516.019.121.03.918.64.0
It is evident from the above two decay tables that more than 35 MeV of energy is deposited by one 227Ac decay chain, representing a significant toxicity risk for essentially the entire lifetime of any human subject administered with 227Ac.
Based on radium-223 production from a 227Ac source, actinium-227 (half-life=21.8 years) is the only likely radionuclide contaminant with a long half-life. Limits for allowed intake of different radionuclides by healthy workers are proposed by the International Commission of Radiological Protection (ICRP) and maximum allowable exposure can be calculated based upon this recommendation and proposed therapeutic doses. The upper limit for actinium-227 is suggested to be 50% of the most restrictive ALI value for oral intake of actinium-227. This gives 0.0045% activity based on a total dose of 300 kBq/kg b.w. (for example 50 kBq/kg b.w.×6 injections) and a patient weight of 80 kg.
In view of the above, the content of 227Ac contaminant in 223Ra for pharmaceutical use should be strictly limited to 45 Bq 227Ac in 1 MBq 223Ra. Thus for practical purposes, a method which is to provide 223Ra for pharmaceutical use should preferably provide a purity of 10 Bq 227Ac in 1 MBq 223Ra or better to ensure that this safety limit is always adhered to.
A number of studies into the purification of 223Ra have been published, primarily in environmental contexts, where the authors desire to accumulate the 223Ra from a high-volume sample so as to allow analysis of the degree of environmental contamination.
Only one previously published method is known to have directly addressed the question of generating 223Ra with biomedical purity, and that is the method of Larsen et al. published in WO/2000/040275. In this method, the involved to permanent absorption of 227Ac and 227Th onto an f-block specific Silica Actinide Resin having P,P′ di-octyl methane bisphosphonic acid binding groups on a silica support. This provided relatively high purity, of less than 4×10−3% 227Ac in comparison with 223Ra, but required a large number of manual handling steps and was poorly suited for scaling-up or automation. Furthermore, because the resin irreversibly absorbed the mother and grandmother nuclei, the issue of radioactive damage to the resin becomes significant if such a resin is to be used for the commercial lifetime of an 227Ac source (tens of years). This is especially the case on a commercial scale, where concentrations of isotopes need to be kept as high as possible to maximise batch sizes and minimise handling volumes.
No previously known method for the generation of 223Ra addresses issues such as yield of 223Ra, speed of the purification process, automation, minimising of wasted isotopes and corresponding production or radioactive waste or any similar issues associated with commercial-scale production. Furthermore, all methods known to produce 223Ra of viable pharmaceutical purity use specialist resins which cannot be guaranteed to be available and are potentially more difficult to validate as reliable. Guseva et al. (Radiochemistry 46, 58-62 (2004)) proposed a basic generator system for 223Ra using an anion exchange method developed for extracting radium from environmental samples. This, however, was on a very small scale and never intended or indicated as providing material of pharmaceutical purity.
One other method for selective binding of f-block elements which has been applied to the purification of lanthanides/actinides from radium is that of Horwitz in U.S. Pat. No. 7,553,461. U.S. Pat. No. 7,553,461 describes a diglycomide (DGA) extractant which can be attached to a resin and used to separate f-block elements from those of the main group. Unlike the actinide resin previously discussed, this extractant allows for the regeneration of an f-block generator mixture after separation and thus does not require that the resin be stable in perpetuity. Because the f-block elements can be released, Horwitz describes this as a method for removing cations such as radium from f-block elements where the radium is considered a contaminant. The radium is washed through a column of DGA resin and disposed of leaving the purified and decontaminated actinide element to be stripped from the column.
The DGA resin described in Horwitz is only demonstrated to provide a separation efficiency of 102 for 223Ra over 227Ac (U.S. Pat. No. 7,553,461, column 19 line 9). This is in the context of removing the radium and this it is not clear how applicable this would be to the preparation of radium rather than actinium, but even if this separation efficiency applied, it would fall well short of the at least 104 separation efficiency required to prepare pharmaceutical standard 223Ra from a 227Ac generator mixture. Thus, if the resin described in U.S. Pat. No. 7,553,461 were used then this would apparently require two consecutive columns.
In view of the above, there is a considerable need for an improved method by which 223Ra may be generated and purified for pharmaceutical use at a purity appropriate for direct injection into human subjects. It would be a considerable advantage if the method were to provide a high yield of 223Ra, a low loss of 227Ac or 227Th parent isotopes and/or utilise only a small number of separation steps. It would be further advantageous if the method was rapid, was viable for relatively large (commercial scale) radioactive samples, included only a minimum number of manual handling steps, and/or was suitable for automation.